Thromb Haemost 2020; 120(10): 1395-1406
DOI: 10.1055/s-0040-1714214
Coagulation and Fibrinolysis

Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients

Iris Garcia-Martínez*
1   Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Nina Borràs*
1   Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Marta Martorell
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Rafael Parra
1   Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Carme Altisent
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Lorena Ramírez
1   Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
,
Maria Teresa Álvarez-Román
3   Thrombosis and Haemostasis Unit, Hospital Universitario La Paz, Madrid, Spain
,
Ramiro Nuñez
4   Hemophilia Unit, Hospital Universitario Virgen del Rocío Sevilla, Sevilla, Spain
,
Juan Eduardo Megias-Vericat
5   Pharmacogenetics Unit of the Pharmaceutical Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain
,
Irene Corrales
1   Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Sofia Alonso
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Francisco Vidal
1   Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
6   CIBER de Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain
› Author Affiliations
Funding This study was funded by Baxalta US Inc., a Takeda company (grant: H16-32623). This study was also supported by the Spanish Ministry of the Economy and Competitiveness (MINECO, Ministerio de Economía y Competitividad), Instituto de Salud Carlos III (ISCIII) (PI15/01643).

Abstract

The pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

Authors' Contributions

F.V., R.P., and M.M. developed the hypothesis, designed the research, and revised the manuscript. R.P., M.M., S.A., C.A., M.T.A-R, R.N., and J.E.M-V. recruited the samples from hemophilic patients included in this study. N.B. selected the SNVs analyzed based on data from the related literature. L.R. performed the molecular analyses. I.G-M. and N.B. identified the SNVs. I.G-M. designed and performed the statistical analyses. I.G-M. and N.B. interpreted the results. I.G-M. and N.B. wrote the manuscript. All authors revised the final version of the manuscript.


* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 24 February 2020

Accepted: 04 June 2020

Article published online:
29 July 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 
  • References

  • 1 Castaman G, Matino D. Hemophilia A and B: molecular and clinical similarities and differences. Haematologica 2019; 104 (09) 1702-1709
  • 2 Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol 2002; 55 (01) 1-18
  • 3 Cafuir LA, Kempton CL. Current and emerging factor VIII replacement products for hemophilia A. Ther Adv Hematol 2017; 8 (10) 303-313
  • 4 Fischer K, Pendu R, van Schooten CJ. , et al. Models for prediction of factor VIII half-life in severe haemophiliacs: distinct approaches for blood group O and non-O patients. PLoS One 2009; 4 (08) e6745
  • 5 Björkman S, Folkesson A, Berntorp E. In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting. Haemophilia 2007; 13 (01) 2-8
  • 6 Collins PW, Björkman S, Fischer K. , et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost 2010; 8 (02) 269-275
  • 7 Hazendonk HCAM, van Moort I, Mathôt RAA. , et al; OPTI-CLOT study group. Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play?. Blood Rev 2018; 32 (04) 265-271
  • 8 Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård U, van den Berg HM. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109 (11) 4693-4697
  • 9 Orstavik KH, Magnus P, Reisner H, Berg K, Graham JB, Nance W. Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985; 37 (01) 89-101
  • 10 Souto JC, Almasy L, Borrell M. , et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101 (13) 1546-1551
  • 11 de Lange M, Snieder H, Ariëns RA, Spector TD, Grant PJ. The genetics of haemostasis: a twin study. Lancet 2001; 357 (9250): 101-105
  • 12 Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet 2005; 6 (06) 488-501
  • 13 Morange PE, Tregouet DA, Frere C. , et al. Biological and genetic factors influencing plasma factor VIII levels in a healthy family population: results from the Stanislas cohort. Br J Haematol 2005; 128 (01) 91-99
  • 14 Song J, Chen F, Campos M. , et al. Quantitative influence of ABO blood groups on factor VIII and its ratio to von Willebrand factor, novel observations from an ARIC study of 11,673 subjects. PLoS One 2015; 10 (08) e0132626
  • 15 Conlan MG, Folsom AR, Finch A. , et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70 (03) 380-385
  • 16 O'Donnell J, Laffan MA. The relationship between ABO histo-blood group, factor VIII and von Willebrand factor. Transfus Med 2001; 11 (04) 343-351
  • 17 Albánez S, Ogiwara K, Michels A. , et al. Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms. J Thromb Haemost 2016; 14 (05) 953-963
  • 18 Miller CH, Haff E, Platt SJ. , et al. Measurement of von Willebrand factor activity: relative effects of ABO blood type and race. J Thromb Haemost 2003; 1 (10) 2191-2197
  • 19 Sousa NC, Anicchino-Bizzacchi JM, Locatelli MF, Castro V, Barjas-Castro ML. The relationship between ABO groups and subgroups, factor VIII and von Willebrand factor. Haematologica 2007; 92 (02) 236-239
  • 20 Lee HY, Park MJ, Kim NY, Yang WI, Shin KJ. Rapid direct PCR for ABO blood typing. J Forensic Sci 2011; 56 (Suppl. 01) S179-S182
  • 21 Shima M, Fujimura Y, Nishiyama T. , et al. ABO blood group genotype and plasma von Willebrand factor in normal individuals. Vox Sang 1995; 68 (04) 236-240
  • 22 Tang W, Cushman M, Green D. , et al. Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. Am J Hematol 2015; 90 (06) 534-540
  • 23 Hermanns MI, Grossmann V, Spronk HM. , et al. Distribution, genetic and cardiovascular determinants of FVIII:c - Data from the population-based Gutenberg Health Study. Int J Cardiol 2015; 187: 166-174
  • 24 Swystun LL, Notley C, Georgescu I. , et al. The endothelial lectin clearance receptor CLEC4M binds and internalizes factor VIII in a VWF-dependent and independent manner. J Thromb Haemost 2019; 17 (04) 681-694
  • 25 Pegon JN, Kurdi M, Casari C. , et al. Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5. Haematologica 2012; 97 (12) 1855-1863
  • 26 Lenting PJ, VAN Schooten CJ, Denis CV. Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost 2007; 5 (07) 1353-1360
  • 27 Antoni G, Oudot-Mellakh T, Dimitromanolakis A. , et al. Combined analysis of three genome-wide association studies on vWF and FVIII plasma levels. BMC Med Genet 2011; 12: 102
  • 28 Smith NL, Chen MH, Dehghan A. , et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121 (12) 1382-1392
  • 29 Cushman M, Yanez D, Psaty BM. , et al; Cardiovascular Health Study Investigators. Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Am J Epidemiol 1996; 143 (07) 665-676
  • 30 Björkman S, Oh M, Spotts G. , et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood 2012; 119 (02) 612-618
  • 31 Vlot AJ, Mauser-Bunschoten EP, Zarkova AG. , et al. The half-life of infused factor VIII is shorter in hemophiliac patients with blood group O than in those with blood group A. Thromb Haemost 2000; 83 (01) 65-69
  • 32 McEneny-King A, Chelle P, Henrard S, Hermans C, Iorio A, Edginton AN. Modeling of body weight metrics for effective and cost-efficient conventional factor VIII dosing in hemophilia a prophylaxis. Pharmaceutics 2017; 9 (04) E47
  • 33 Carcao MD, Chelle P, Clarke E. , et al. Comparative pharmacokinetics of two extended half-life FVIII concentrates (Eloctate and Adynovate) in adolescents with hemophilia A: Is there a difference?. J Thromb Haemost 2019; 17 (07) 1085-1096
  • 34 Björkman S, Blanchette VS, Fischer K. , et al; Advate Clinical Program Group. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost 2010; 8 (04) 730-736
  • 35 Swystun LL, Ogiwara K, Rawley O. , et al. Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients. Blood 2019; 134 (11) 880-891
  • 36 Bolon-Larger M, Chamouard V, Bressolle F, Boulieu R. A limited sampling strategy for estimating individual pharmacokinetic parameters of coagulation factor VIII in patients with hemophilia A. Ther Drug Monit 2007; 29 (01) 20-26
  • 37 Auton A, Brooks LD, Durbin RM. , et al; 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 2015; 526 (7571): 68-74
  • 38 Akaike H. A new look at the statistical model identification. IEEE Trans Automat Contr 1974; 19 (06) 716-723
  • 39 Jennings I, Kitchen DP, Woods TA, Kitchen S, Walker ID. Emerging technologies and quality assurance: the United Kingdom National External Quality Assessment Scheme perspective. Semin Thromb Hemost 2007; 33 (03) 243-249
  • 40 Kitchen S, Jennings I, Makris M, Kitchen DP, Woods TAL, Walker ID. Clotting and chromogenic factor VIII assay variability in post-infusion and spiked samples containing full-length recombinant FVIII or recombinant factor VIII Fc fusion protein (rFVIIIFc). Int J Lab Hematol 2019; 41 (02) 176-183
  • 41 Renaud O, Victoria-Feser M-P. A robust coefficient of determination for regression. J Stat Plan Inference 2010; 140 (07) 1852-1862
  • 42 Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol 1995; 57: 289-300
  • 43 Zabaneh D, Gaunt TR, Kumari M. , et al. Genetic variants associated with Von Willebrand factor levels in healthy men and women identified using the HumanCVD BeadChip. Ann Hum Genet 2011; 75 (04) 456-467
  • 44 Jenkins PV, O'Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?. Transfusion 2006; 46 (10) 1836-1844
  • 45 McGrath RT, McKinnon TA, Byrne B. , et al. Expression of terminal alpha2-6-linked sialic acid on von Willebrand factor specifically enhances proteolysis by ADAMTS13. Blood 2010; 115 (13) 2666-2673
  • 46 Lalezari S, Martinowitz U, Windyga J. , et al. Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS. Haemophilia 2014; 20 (01) e15-e22
  • 47 Iorio A, Maas Enriquez M, Delesen H. , et al. Correlations between von Willebrand factor antigen levels and factor VIII pharmacokinetics are similar across different FVIII products in patients with severe hemophilia A. Blood 2019; 134 (Suppl. 01) 3637
  • 48 Björkman S. Comparative pharmacokinetics of factor VIII and recombinant factor IX: for which coagulation factors should half-life change with age?. Haemophilia 2013; 19 (06) 882-886
  • 49 Kepa S, Horvath B, Reitter-Pfoertner S. , et al. Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A. Haemophilia 2015; 21 (03) 343-350
  • 50 van Dijk K, van der Bom JG, Lenting PJ. , et al. Factor VIII half-life and clinical phenotype of severe hemophilia A. Haematologica 2005; 90 (04) 494-498
  • 51 Sabater-Lleal M, Huffman JE, de Vries PS. , et al; INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC). Genome-wide association transethnic meta-analyses identifies novel associations regulating coagulation factor VIII and von Willebrand factor plasma levels. Circulation 2019; 139 (05) 620-635
  • 52 Iorio A, Edginton AN, Blanchette V. , et al. Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: rationale and general considerations. Res Pract Thromb Haemost 2018; 2 (03) 535-548